Adenosine A2b Receptors Control A1 Receptor-Mediated Inhibition of Synaptic Transmission in the Mouse Hippocampus

Eur J Neurosci. 2015 Apr;41(7):878-88. doi: 10.1111/ejn.12851. Epub 2015 Feb 19.


Adenosine is a neuromodulator mostly acting through A1 (inhibitory) and A2A (excitatory) receptors in the brain. A2B receptors (A(2B)R) are G(s/q)--protein-coupled receptors with low expression in the brain. As A(2B)R function is largely unknown, we have now explored their role in the mouse hippocampus. We performed electrophysiological extracellular recordings in mouse hippocampal slices, and immunological analysis of nerve terminals and glutamate release in hippocampal slices and synaptosomes. Additionally, A(2B)R-knockout (A(2B)R-KO) and C57/BL6 mice were submitted to a behavioural test battery (open field, elevated plus-maze, Y-maze). The A(2B)R agonist BAY60-6583 (300 nM) decreased the paired-pulse stimulation ratio, an effect prevented by the A(2B)R antagonist MRS 1754 (200 nM) and abrogated in A(2B)R-KO mice. Accordingly, A(2B)R immunoreactivity was present in 73 ± 5% of glutamatergic nerve terminals, i.e. those immunopositive for vesicular glutamate transporters. Furthermore, BAY 60-6583 attenuated the A(1)R control of synaptic transmission, both the A(1)R inhibition caused by 2-chloroadenosine (0.1-1 μM) and the disinhibition caused by the A(1)R antagonist DPCPX (100 nM), both effects prevented by MRS 1754 and abrogated in A(2B)R-KO mice. BAY 60-6583 decreased glutamate release in slices and also attenuated the A(1)R inhibition (CPA 100 nM). A(2B)R-KO mice displayed a modified exploratory behaviour with an increased time in the central areas of the open field, elevated plus-maze and the Y-maze and no alteration of locomotion, anxiety or working memory. We conclude that A(2B)R are present in hippocampal glutamatergic terminals where they counteract the predominant A(1)R-mediated inhibition of synaptic transmission, impacting on exploratory behaviour.

Keywords: A1 receptors; A2B receptor; Adenosine; hippocampus; nerve terminal; receptor interaction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 2-Chloroadenosine / pharmacology
  • Acetamides / pharmacology
  • Adenosine A1 Receptor Agonists / pharmacology
  • Adenosine A1 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Agonists / pharmacology
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Aminopyridines / pharmacology
  • Animals
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Glutamic Acid / metabolism
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Purines / pharmacology
  • Receptor, Adenosine A1 / metabolism*
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Vesicular Glutamate Transport Proteins / metabolism
  • Xanthines / pharmacology


  • Acetamides
  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Aminopyridines
  • BAY 60-6583
  • N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide
  • Purines
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2B
  • Vesicular Glutamate Transport Proteins
  • Xanthines
  • 2-Chloroadenosine
  • Glutamic Acid
  • 1,3-dipropyl-8-cyclopentylxanthine